PROJECT 1: Acute and Long Term Immune Responses to Radiation and Mitigation PROJECT SUMMARY The long-term goal of this application is to understand the role of immune responses in and the mechanisms responsible for the short and long term diseases caused by exposure to sources of ionizing radiation. One important aspect of radiation injury is the release of both endogenous damage associated molecular patterns (DAMPs) from the damaged tissues and pathogen associated molecular patterns (PAMPs) from the gastrointestinal system. These DAMPs and PAMPs released after irradiation interact with common pattern recognition receptors such as Toll-Like Receptors (TLR) and activate overlapping gene programs to regulate innate and adaptive immune responses as well as tissue damage and repair. In our previous studies, we found that MIS416 ? a particle based on the cell wall components of P. acnes decorated with a single stranded TLR9 ligand CpG-A (Vironyx Corp.) ? which likely contains multiple PAMPs, can function as a mitigator to rescue lethally irradiated mice. We have further evidence that different TLR agonists induce different profiles of growth factors, cytokines and chemokines, suggesting that multiple innate immune pathways might be required to mitigate radiation damage. Based on our results from multiple tissue damage models, we have recently hypothesized that over reactive innate immune responses to DAMPs and PAMPs released after irradiation can further trigger secondary tissue damages by proinflammatory cytokines and autoantibodies. We have further developed a widely available and easily deliverable DAMP blocking compound, glycyrrhizic acid (GA), as a potent radiation mitigator. In addition, while GCSF has been used as a standard mitigator, we have developed a bivalent GCSF (Bi-GCSF) as a more potent and stable radiation mitigator. Through close collaboration with Dr. William McBride's group, we have found that although many mitigators can effectively rescue lethally irradiated mice during acute radiation syndrome (ARS), many rescued mice often develop delayed effects of acute radiation exposure (DEARE) exhibiting chronic diseases such as heart and kidney failures around a year after WBI. Our preliminary studies indicate that these chronic diseases are associated with proinflammatory responses. Based on these studies, we hypothesize that balanced immune and inflammatory responses are critical not only for rescuing acute phase tissue damages but also for preventing chronic diseases caused by radiation. In this application, we will evaluate the effects of individual mitigators on the short and long term innate and adaptive immune systems and further develop a combination of mitigators that can effectively treat both acute and chronic diseases after radiation.